Antidepressant dosage form

ABSTRACT

A dosage form having sustained-release or controlled-release properties for delivering 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol from the dosage form over an extended period of time in a therapeutically responsive dose to produce antidepressant therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/522,014, filed Sep. 15, 2006, which is a continuation of U.S.application Ser. No. 10/696,370, filed Oct. 28, 2003, abandoned, and acontinuation of U.S. application Ser. No. 11/315,434, filed Dec. 22,2005, abandoned, each of which is a continuation of U.S. applicationSer. No. 08/442,292, filed May 16, 1995, abandoned, which is adivisional application claiming benefit of U.S. application Ser. No.08/068,480, filed May 27, 1993, which issued as U.S. Pat. No. 6,440,457on Aug. 27, 2002. U.S. application Ser. Nos. 11/522,014, 10/696,370,11/315,434, and 08/442,292 are incorporated by reference herein in theirentirety.

FIELD OF THE INVENTION

This invention pertains to a controlled-release dosage form comprising acompound of the following structural formula:

useful for antidepressant therapy. The invention concerns also a methoduseful for antidepressant therapy by administering thecontrolled-release dosage form comprising the compound of the formula.

BACKGROUND OF THE INVENTION

The primary goal of drug administration is to provide a therapeutic doseof drug in the body to achieve a desired blood concentration, and thenmaintain the desired drug blood concentration. The prior art, inattempts to obtain the desired therapeutic effect, often used differentdosage forms or programs. One dosage program consists of a single dosingof the drug from a conventional capsule or tablet that produced a rapidrise followed by an immediate decline of the drug blood level versustime The single dosing does not maintain the drug within a therapeuticrange for an extended period of time, but exhibits of a short durationof action due to the inability of the conventional dosage form toprovide drug delivery over time.

Another prior art dosing program used to obtain and to achieve drugblood levels consists in administering the drug repetitively usingconventional dosage forms at various dosing intervals, as inmultiple-dose therapy. In administering a drug according to themultiple-dose therapy, the drug blood level reached and the timerequired to reach that level depends on the dose and the dosinginterval. There are, however, several potential problems inherent inmultiple dose therapy. For example, if the dosing interval is notappropriate for the biological half-life of the drug, large peaks andvalleys may result in the drug blood levels. Also, the drug blood levelmay not be within the therapeutic range at sufficiently early times, animportant consideration for many disease states. And too, patientnoncompliance with the multiple dosing regimen can result in a failureof this approach, especially as a drug in circulation surges to a higheach time the drug is administered followed by a decline in drugconcentration in the blood and in body compartments. Thus, a graph ofdrug in circulation following a dosage program of several doses, has anappearance of a series of peaks, which may surpass the toxic threshold.Then, each time the blood levels decreases into valleys, below acritical level needed to achieve a desired therapeutic effect, thateffect may not be obtainable in the blood and body. Conventional dosageforms and their mode of operation are discussed in Remington'sPharmaceutical Sciences, 18th Edition, pages 1676 to 1686, (1990), MackPublishing Co.; The Pharmacological Basis of Therapeutics, 7th Edition,page 7 (1985) published by MacMillian Publishing Co., and in U.S. Pat.Nos. 3,598,122 and 3,598,123 both issued to Zaffaroni.

A critical need exists for a controlled-rate dosage form foradministering the drug of the formula:

which drug is presently administered in conventional dosage formsincluding tablets, capsules, elixirs and suspensions. These conventionaldosage forms produce the peaks and valleys drug pattern presented aboveand they do not provide for controlled-rate therapy over an extendedperiod of time. The drug of the formula is dosed twice or thrice a daynow because of its elimination half-life of three to five hours. Thispattern of dosing indicates the need for a controlled-release dosageform that can administer the drug at a controlled rate over an extendedtime to provide constant therapy and thereby eliminate the need formultiple dosing. The drugs of the structural formula are known in U.S.Pat. Nos. 4,535,186; 4,611,078; and 4,761,501 all issued to Husbands,Yardley and Muth.

The prior art provided controlled-release dosage forms that cancontinuously over time administer a drug for controlled-rate therapy.For example, in U.S. Pat. No. 4,327,725 issued to Cortese and Theeuwesand in U.S. Pat. Nos. 4,612,008; 4,765,989; and 4,783,337 issued toWong, Barclay, Deters, and Theeuwes. The dosage forms disclosed in thesepatents provide a drug at a constant rate for effecting a therapeuticrange for preferred therapy. The dosage forms of the patents provide atherapeutic range and avoids delivering the drug in excess in a toxicrange with its accompanying side-effects. The dosage forms of thepatents in providing a controlled dose in a therapeutic range alsoavoids delivering the drug in an ineffective dose in an ineffectiverange.

The dosage forms presented immediately above operate successfully fortheir intended use and they can deliver many drugs indicated for goodtherapy. The drugs of the above structural formula, however, possessproperties such as a high solubility of 570 mg per ml at a bodytemperature of 37° C. that can lead to a premature release of the drugfrom the dosage form. During operation of the dosage forms, theconvection motion of the imbibed fluid, and the hydrostatic pressure ofthe imbibed fluid coupled with the high solubility can result in thepremature release of the drugs of the formula.

It is immediately apparent in the light of the above presentation thatan urgent need exists for a dosage form endowed with controlled-releasedelivery for delivering the drugs embraced by the structural formula.The need exists for the dosage form for delivering the drug at acontrolled dose in a therapeutic range while simultaneously providingthe intended therapy. It will be appreciated by those versed in thedispensing art, that such a dosage form that can administer the drug ina controlled-rate dose over time, would, represent an advancement and avaluable contribution to the art.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a dosage form that possessescontrolled-release delivery for providing a dosage form foradministering a drug of the structural formula.

Another object of the present invention is to provide a dosage form foradministering the drug of the formula in a controlled-rate dose in atherapeutic range over a prolonged period of time.

Another object of the present invention is to provide a dosage form thatcan deliver the drug of the formula essentially-free of a prematurerelease from the dosage form.

Another object of the present invention is to provide a drug deliverycontrolled-release system that can deliver a drug for maintainingconstant drug levels in the blood thereby functioning as a prolongedrelease system.

Another object of the present invention is to provide drug deliverysustained-release system that provides slow release of the drug over anextended period of time optionally in a therapeutic range.

Another object of the present invention is to provide a dosage form thatsubstantially reduces and/or substantially eliminates the unwantedinfluences of a gastrointestinal environment of use and still providescontrolled drug administration.

Another object of the present invention is to provide an improvement ina dosage form for administering a drug embraced by the structuralformula and its pharmaceutically acceptable salt, wherein theimprovement comprises delivering the drug in a controlled-release ratefrom the dosage form for improved and known therapy.

Another object of the invention is to provide a once-a-daycontrolled-release dosage form to deliver the drug of the structuralformula orally to a patient in need of therapy.

Another object of the invention is to provide a method for administeringa drug of the formula by orally administering the drug in a controlledrate dose per unit dose over an extended time to an animal in need oftherapy.

Another object of the present invention is to provide a method foradministering a drug of the formula in a therapeutic range whilesimultaneously substantially avoiding a toxic range and an infectiverange.

Another object of the present invention is to provide a therapeuticcomposition comprising a drug of the structural formula blended with adrug-composition-forming polymer.

Another object of the invention is to provide a therapeutic compositioncomprising a member selected from the group consisting of venlafaxineand its pharmaceutically acceptable additional salt and apharmaceutically acceptable polymer carrier for venlafaxine and itsacceptable salts.

Other objects, features, and advantages of the invention will be moreapparent to those versed in the dispensing arts from the followingdetailed specification, taken in conjunction with the drawings and theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

Drawing FIG. 1 is a general view of a dosage form provided by theinvention, which dosage form is designed and shaped for oraladministration, and for a drug delivery in a controlled-rate dose in thegastrointestinal tract;

Drawing FIG. 2 is an opened view of the dosage form of drawing FIG. 1for depicting the structure of the dosage form and the compositionmember contained inside the dosage form; and

Drawing FIG. 3 is a view of a dosage form that depicts an external,instant-release of drug of the structural formula coated on the exteriorsurface of the dosage form.

In the drawing figures, and in the specification, like parts in relatedfigures are identified by like numbers. The terms appearing earlier inthe specification and in the description of the drawing figures, as wellas embodiments thereof, are further described elsewhere in thedisclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawing figures in detail, which drawing figures areexamples of dosage forms provided by this invention, and which examplesare not to be construed as limiting, one example of a dosage form isseen in drawing FIG. 1. In drawing FIG. 1, a dosage form 10 is seencomprising a body member 11, which body 11 comprises wall 12, thatsurrounds and forms an internal area, not seen in drawing FIG. 1. Dosageform 10 comprises at least one exit port 13 for connecting the exteriorwith the interior of dosage form 10.

The dosage form 10 of drawing FIG. 1 illustrates a controlled-releasedosage form manufactured as an osmotic dosage form that delivers a drugby osmotic action over an extended period of time. The dosage formcomprising controlled-release properties embraced by this invention aresuccessful at maintaining substantially constant drug levels in theblood or in a tissue. The dosage forms within the mode and manner ofthis invention comprises also sustained-release dosage forms. Thesustained-release dosage forms releases the drug and provide drug levelsin the blood or target tissue within a therapeutic range over anextended period of time. The invention embraces additionally prolongedrelease dosage forms. The prolonged release dosage form denotes extendedduration of drug delivery action over that achieved by conventional drugdelivery.

In drawing FIG. 2, dosage form 10 of FIG. 1 is seen in opened section.In drawing FIG. 2, dosage form 10 comprises a body 11, a wall 12 thatsurrounds and defines an internal compartment 14. In drawing FIG. 2,internal compartment 14 communicates through an exit passageway 13 withthe exterior of dosage form 10.

Wall 12 of dosage form 10 comprises totally or in at least a part of acomposition that is permeable to the passage of an exterior fluidpresent in an environment of use, such as aqueous and biological fluids.Wall 12 is formed of nontoxic ingredients, is substantially impermeableto the passage of a drug and other ingredients present in compartment14. Wall 12 comprises a composition that is substantially inert, thatis, wall 12 maintains its physical and chemical integrity during thedrug dispensing life of a drug from dosage form 10. The phrase,“maintaining its physical and chemical integrity,” means wall 12 doesnot lose its structure and it does not change during the dispensing lifeof dosage form 10, except for possible leaching of one or more exit 13passageway formed during operation of dosage form 10 or for leaching awater-soluble flux enhancers blended into wall 12. Wall 12 comprises amaterial that does not adversely affect an animal, a human or any othercomponents comprising the dosage form. Representative materials forforming wall 12, are in one embodiment, a cellulose ester polymer, acellulose ether polymer and a cellulose esterether polymer. Thesecellulosic polymers have a degree of substitution, D.S., on theanhydroglucose unit, from greater than 0 up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups originallypresent on the anhydroglucose unit comprising the cellulose polymer thatare replaced by a substituting group. Representative materials include amember selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono-, di- and tricellulosealkanylates, mono-, di-, and tricellulose aroylates, and the like.Exemplary polymers include cellulose acetate having a D.S. up to 1 andan acetyl content up to 21%; cellulose acetate having a D.S. of 1 to 2and an acetyl content of 21 to 35%; cellulose acetate having a D.S. of 2to 3 and an acetyl content of 35 to 44.8%, and the like. More specificcellulosic polymers include cellulose propionate having a D.S. of 1.8and a propyl content of 39.2 to 45% and a hydroxyl content of 2.8 to5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl contentof 13 to 15% and a butyryl content of 34 to 39%; cellulose acetatebutyrate having an acetyl content of 2 to 29%, a butyryl content of 17to 53% and a hydroxyl content of 0.5 to 4.7; cellulose triacylateshaving a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate, andcellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentanoate, co-esters of cellulose such ascellulose acetate butyrate and cellulose acetate propionate, and thelike.

Additional polymers include ethyl cellulose of various degree ofetherification with ethoxy content of from 40% to 55%, acetaldehydedimethyl cellulose acetate, cellulose acetate ethyl carbamate, celluloseacetate methyl carbamate, cellulose acetate diethyl aminoacetate,semipermeable polyamides; semipermeable polyurethanes; semipermeablesulfonated polystyrenes; semipermeable cross-linked selective polymersformed by the coprecipitation of a polyanion and a polycation asdisclosed in U.S. Pat. Nos. 3,173,876, 3,276,586, 3,541,005; 3,541,006,and 3,546,142; semipermeable polymers as disclosed by Loeb andSourirajan in U.S. Pat. No. 3,133,132; semipermeable lightlycross-linked polystyrene derivatives, semipermeable cross-linkedpoly(sodium styrene sulfonate); semipermeable cross-linkedpoly(vinylbenzyltrimethyl ammonium chloride); semipermeable polymersexhibiting a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻⁴ (cm²/hr·atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. The polymers are known to the art in U.S.Pat. Nos. 3,845,770; 3,916,899; and 4,160,020; and in Handbook of CommonPolymers by Scott, J. R. and Roff, W. J., 1971 published by CRC Press,Cleveland, Ohio.

Compartment 14 comprises a drug composition, identified as drug layer 15which contains drug 16, identified by dots. Drug 16 comprises a drug ofthe following structural formula:

wherein the dotted line represents optional unsaturation or acycloalkenyl moiety; R₁ is a member selected from the group consistingof hydrogen and alkyl of 1 to 6 carbon atoms; R₂ is a member selectedfrom the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;R₄ is a member selected from the group consisting of hydrogen, alkyl of1 to 6 carbon atoms, formyl, and alkanoyl of 2 to 7 carbon atoms; R₅ andR₆ are independently a member selected from the group consisting ofhydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1 to 6carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro, alkylmercaptoof 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms inwhich each alkyl group comprises 1 to 6 carbon atoms, alkanamido of 2 to7 carbon atoms, halo, and trifluoroethyl, R₇ is a member selected fromthe group consisting of hydrogen and alkyl of 1 to 6 carbons, and n isone of the integers 0, 1, 2, 3, and 4. The formula embraces also thepharmaceutically acceptable addition salts including a member selectedfrom the group consisting of inorganic, organic, hydrochloric,hydrobromic, gluconic, fumaric, maleric, sulfonic, succinic, sulfuric,phosphoric, tartaric, acetic, proponic, citric, oxalic and similarpharmaceutically acceptable addition salts. The compounds are known inU.S. Pat. Nos. 4,535,186; 4,611,078; 4,761,501; and 5,190,765.

The drugs of the structural formula are represented by the drug1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol of thestructural formula:

The drug embraced by the formula possesses antidepressant properties.The drug in vitro prevents the neuronal uptake of serotonin,morepinephrine, and dopamine and it does not inhibit monoamine oxidase.The drug antagonizes reserpine-induced hypothermia and potentiates theeffects of levodopa, and reduces histamine-induced corticotropin releaseand induces cyclicadenosine monophosphate subsensitivity after bothacute and chronic administration. The drug possesses excellentantidepressant activity in humans. The therapeutic amount of drug 16 indosage form 10 is 0.5 mg to 750 mg, with individual dosage formscomprising 2, 5, 10, 25, 40, 50, 75, 100, 150, 250, 300, 500, and 600 mgof drug 16 for administering in a single dose or more than one dose overan extended period of 24 hours. The therapeutic properties of the drugembraced by the structural formula are reported in Current TherapeuticResearch, Vol. 42, No. 5, pages 901 to 909 (1987).

Composition 15 comprising drug 16 may comprise a drug dispensing carrierand composition formulating member consisting of a member selected fromthe group consisting of 0 wt % to 25 wt % of ahydroxypropylalkylcellulose where alkyl consists of 1 to 7 carbonsselected from the group consisting of methyl, ethyl, isopropyl, butyl,pentyl, and hexyl which cellulose member comprises a 9,000 to 1,250,000molecular weight and is exemplified by hydroxypropylmethylcelluose,hydroxypropylethylcellulose, hydroxypropylisopropylcellulose,hydroxypropylbutylcellulose and hydroxypropylhexylcellulose representedby dashes 17; a member selected from the group consisting of 0 wt % to20 wt % hydroxylalkylcellulose where alkyl is 1 to 6 carbons includingmethyl, ethyl, propyl, butyl, pentyl, and hexyl which cellulose membercomprises a 7,500 to 750,000 molecular weight and is exemplified byhydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyisopropylcellulose and hydroxybutylcellulose as represented byslanted line 18; a member selected from the group consisting of 0 wt %to 35 wt % of a vinyl-polymer having a 3,500 to 750,000 molecular weightrepresented by poly-n-vinylamide, poly-n-vinylcetamide,poly-n-vinylethylacetamide, poly-n-vinylmethylpropionamide, poly-n-vinylethylpropionamide, poly-n-vinylmethylisobutyramide,poly-n-vinyl-2-pyrrolidone, poly-n-vinypiperidone also known aspolyvinylpyrrolidone and as poly-n-vinylpyrroledone,poly-n-vinylcaprolactam, poly-n-vinyl-5-methyl-2-pyrrolidone andpoly-n-vinyl-3-methyl-2-pyrrolidone, and poly-n-vinylpyrrolidonecopolymer with a member selected from the group consisting of vinylacetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate,vinyl laurate and vinyl stearate represented by small circles 19; and 0wt %, where wt % is weight percent, to 35 wt % of a maltodextrin polymercomposition comprising the formula (C₆H₁₂0₅)_(n) H₂0 wherein n is 3 to7,500 and the maltodextrin polymer comprises a 500 to 1,250,000 numberaverage molecular weight represented by a small square 20; as memberselected from the group consisting of 0 wt % to 40 wt % of poly(etheylenoxide) having a molecular weight of 100,000 to 600,000 grams per mole,represented by half-circles 20 a. Composition 15 optionally comprisesfrom 0 to 4.5 wrio of a lubricant represented by magnesium stearate,calcium stearate or stearic acid. The total weight of all ingredients incomposition 15 is equal to 100 wt %, weight percent.

Compartment 14 comprises a displacement composition or push layer 21.Displacement composition 21 comprises a polymer member selected from thegroup consisting of a polymer possessing a repeating molecular unit(-0-CH₂CH₂—)_(n) wherein n is a positive whole number of 50,000 to300,000 as represented by a poly(alkylene oxide) comprisingpoly(ethylene oxide) seen as wavy line 22; a maltodextrin polymer of theformula (C₆H₁₂0₅)_(n) H₂0 wherein n is 50 to 62,000 and comprises a9,000 to 10,000,000 molecular weight and represented by triangle 23; acarboxymethylcellulose polymer comprising a 10,000 to 5,000,000molecular weight represented by alkali carboxymethylcellulose, sodiumcarboxymethylcellulose and potassium carboxymethylcellulose, ammoniumcarboxymethylcellulose, sodium carboxymethyl-2-hydroxyethylcellulose,sodium carboxymethyl-methylcellulose, alkalicarboxymethyl-hydroxypropyl-methylcellulose, alkalicarboxymethyl-2-hydroxyethylmethylcellulose, alkalicarboxymethyl-2-hydroxybutylmethylcellulose, alkalicarboxymethyl-2-hydroxyethyl-ethylcellulose and alkalicarboxymethyl-2-hydroxypropylcellulose, where alkali is sodium andpotassium and seen in drawing FIG. 2 as hexagonal 23 a. The polymers inpush layer 21 provide unforeseen operating advantages as the polymermaintains its chemical composition during operation as it imbibes anexternal aqueous fluid including biological fluid while simultaneouslypushing the drug from the dosage form essentially free of substantiallymixing the drug composition with the push composition. The displacementcomposition 21 comprises optionally from 4 to 35 wt % of an osmoticallyactive compound, also known as osmagent and represented by vertical line24. Representative of osmotically effective compounds comprises salts,oxides, esters that exhibit imbibition properties, carbohydrates andacids including a member selected from the group consisting of magnesiumsulfate, magnesium chloride, sodium chloride, lithium chloride,potassium chloride, potassium sulfate, sodium sulfate, sodium sulfite,lithium sulfate, ammonium chloride, potassium lactate, mannitol, urea,magnesium succinate, tartaric acid, raffinose, sorbitol, sucrose,fructose, and glucose. Displacement layer 21 optionally comprises 0.5 wt% to 30 wt % of a cellulose polymer 25 represented by the letter v.Representative of cellulose polymer 25 comprise a member selected fromthe group consisting of hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxypropylethylcellulose,hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose,hydroxypropylpentylcellulose, and hydroxypropylhexylcellulose comprisinga 9,000 to 225,000 molecular weight. The displacement compositionoptionally comprises 0 wt % to 5 wt % of lubricant stearic acid and,magnesium stearate, calcium oleate, oleic acid, and caprylic acid. Thepolymers are known in U.S. Pat. Nos. 3,845,770; and 4,160,020; inHandbook of Common Polymers by Scott, J. R., and Roff, W. J., publishedby CRC Press, Cleveland, Ohio.

Dosage form 10, as seen in drawing FIG. 3 depicts another preferredmanufacture provided by the invention. Dosage form 10, in drawing FIG.3, comprises an external coat on the exterior surface of dosage form 10.Coat 26 is a therapeutic composition comprising 10 mg to 150 mg of drug16, represented by dots 16. Exterior coat 26 provides instant drug 16for instant therapy. Drug 16 is blended with an aqueous-solublecomposition comprising a carrier methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, and blends ofhydroxypropylcellulose and hydroxypropylmethylcellulose. Coat 26optionally comprises polyethylene glycol or acetylated triglycerides.Coat 26 provides instant therapy as coat 26 dissolves or undergoesdissolution in the presence of a biological fluid and concurrentlytherewith delivers drug 16 to a drug receiving patient. Coat 26 providesinstant therapy and it essentially overcomes the time required for thedrug to be delivered from the dosage form.

Dosage form 10, as provided by this invention, and as seen in the abovedrawing figures can be manufactured for administering drug 16 by theoral route, and in another embodiment, dosage form 10 comprisingexterior and interior drug 16 can be sized and shaped for administeringdrug 16 by the sublingual and buccal routes. The sublingual and buccalroutes can be used for quicker therapy and they can be used when asmaller dose of drug 16 is needed for therapy. The buccal and sublingualroutes can be used as a by-pass of the first pass of hepatic metabolismof drug 16. The sublingual or buccal routes can be used foradministering the first dose of drug, followed by permitting dosage form10 to enter the gastrointestinal tract for subsequent drug delivery.

Dosage form 10, when manufactured as an osmotic, controlled-releasedosage form, comprises at least one passageway 13, or more than onepassageway 13. The expression “at least one passageway” includesaperture, orifice, bore, pore, porous element through which the drug canbe pumped, diffuse, travel or migrate, hollow fiber, capillary tube,porous overlay, porous insert, microporous member, porous composition,and the like. The expression also includes a material that erodes or isleached from wall 12 in the fluid environment of use to produce at leastone passageway in dosage form 10. Representative material suitable forforming at least one passageway, or a multiplicity of passageways,includes an erodible poly(glycolic) acid or poly(lactic) acid member inthe wall; a gelatinous filament; poly(vinyl alcohol); leachablematerials such as fluid removable pore forming polysaccharides, salts,or oxides, and the like. A passageway or a plurality of passageways canbe formed by leaching a material such as sorbitol, sucrose, lactose,fructose, or the like, from the wall to provide an osmotic dimensionedpore-passageway. The passageway can have any shape such as round,triangular, square, elliptical, and the like, for assisting in themetered release of drug from dosage form 10. Dosage form 10 can beconstructed with one or more passageways in spaced apart relation on oneor more than a single surface of a dosage form. Passageways andequipment for forming passages are disclosed in U.S. Pat. Nos. 3,845,770and 3,916,899 by Theeuwes and Higuchi; in U.S. Pat. No. 4,063,064 bySaunders et al; and in U.S. Pat. No. 4,088,864 by Theeuwes et al.Osmotic passageways comprising controlled-drug releasing dimension,sized, shaped and adapted as a drug releasing pore formed by aqueousleaching to provide a drug-releasing pore of controlled osmotic releaserate are disclosed in U.S. Pat. No. 4,200,098 by Ayer and Theeuwes; andin U.S. Pat. No. 4,285,987 by Ayer and Theeuwes.

Wall 12 of osmotic dosage form 10 can be formed in one technique usingthe air suspension procedure. This procedure consists in suspending andtumbling the compressed drug-push core laminate in a current of air andwall forming composition until a wall is applied to the drug-pushcompartment. The air suspension procedure is well-suited forindependently forming the wall. The air suspension procedure isdescribed in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., Volume 48,pages 451 to 454, (1959); and ibid, Volume 49, pages 82 to 84, (196).Osmotic dosage forms can also be coated with a wall forming compositionin a Wurster® air suspension coater, using methylene dichloride-methanolcosolvent, 80:20, wt:wt, an ethanol-water, or acetone-water cosolvent,95:5 wt:wt using 2.5 to 4% solids. The Aeromatic® air suspension coaterusing a methylene dichloride-methanol cosolvent, 80:20 wt:wt, also canbe used for applying the wall. Other wall forming techniques such as pancoating system, where wall forming compositions are deposited bysuccessive spraying of the composition on the drug-push compartment,accompanied by tumbling in a rotating pan. Finally, the wall coatedcompartments are dried in a forced air over at 30° C. to 50° C. for upto a week to free dosage form 10 of solvent. Generally, the walls formedby these techniques have a thickness of 2 to 30 mils with a presentlypreferred thickness of 4 to 10 mils.

Dosage form 10 of the invention is manufactured by standardmanufacturing techniques. For example, in one manufacture the beneficialdrug and other ingredients comprising the drug layer facing the exitmeans are blended and pressed into a solid layer. The drug and otheringredients can be blended with a solvent and mixed into a solid orsemisolid formed by conventional methods such as ball-milling,calendering, stirring or rollmilling and then pressed into a preselectedshape. The layer possesses dimensions that correspond to the internaldimensions of the area the layer is to occupy in the dosage form and italso possesses dimensions corresponding to the second layer for forminga contacting arrangement therewith. Next, the push layer, is placed incontact with the drug layer. The push layer is manufactured usingtechniques for providing the drug layer. The layering of the drug layerand the push layer can be fabricated by conventional press-layeringtechniques. Finally, the two layer compartment forming members aresurrounded and coated with an outer wall. A passageway is laser,leached, or mechanically drilled through the wall to contact the druglayer, with the dosage form optically oriented automatically by thelaser equipment for forming the passageway on the preselected surfacewhen a laser is used for forming the passageway.

In another manufacture, the dosage form is manufactured by the wetgranulation technique. In the wet granulation technique, for example,the drug and the ingredients comprising the drug layer are blended usingan organic solvent, such as isopropyl alcohol-ethylene dichloride 80:20v:v (volume:volume) as the granulation fluid. Other granulating fluidsuch as denatured alcohol 100% can be used for this purpose. Theingredients forming the drug layer are individually passed through a 40mesh screen and then thoroughly blended in a mixer. Next, otheringredients comprising the drug layer are dissolved in a portion of thegranulation fluid, such as the cosolvent described above. Then thelatter prepared wet blend is slowly added to the drug blend withcontinual mixing in the blender. The granulating fluid is added until awet blend is produced, which wet mass then is forced through a 20 meshscreen onto oven trays. The blend is dried for 18 to 24 hours at 30° C.to 50° C. The dry granules are sized then with a 20 mesh screen. Next, alubricant is passed through an 80 mesh screen and added to the dryscreen granule blend. The granulation is put into milling jars and mixedon a jar mill for 1 to 15 minutes. The push layer is made by the samewet granulation techniques. The compositions are pressed into theirindividual layers in a Manesty® press-layer press.

Another manufacturing process that can be used for providing thecompartment-forming composition layers comprises blending the powderedingredients for each layer independently in a fluid bed granulator.After the powdered ingredients are dry blended in the granulator, agranulating fluid, for example, poly(vinyl-pyrrolidone) in water, or indenatured alcohol, or in 95:5 ethyl alcohol/water, or in blends ofethanol and water is sprayed onto the powders. Optionally, theingredients can be dissolved or suspended in the granulating fluid. Thecoated powders are then dried in a granulator. This process granulatesall the ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant such as stearic acid ormagnesium stearate is added to the granulator. The granules for eachseparate layer are pressed then in the manner described above.

The dosage form of the invention is manufactured in another manufactureby mixing a drug with composition forming ingredients and pressing thecomposition into a solid lamina possessing dimensions that correspond tothe internal dimensions of the compartment. In another manufacture thedrug and other drug composition-forming ingredients and a solvent aremixed into a solid, or a semisolid, by conventional methods such asballmilling, calendering, stirring or rollmilling, and then pressed intoa preselected layer forming shape. Next, a layer of a compositioncomprising an osmopolymer and an optional osmagent are placed in contactwith the layer comprising the drug. The layering of the first layercomprising the drug and the second layer comprising the osmopolymer andoptional osmagent composition can be accomplished by using aconventional layer press technique. The wall can be applied by molding,spraying or dipping the pressed bilayer's shapes into wall formingmaterials. Another and presently preferred technique that can be usedfor applying the wall is the air suspension coating procedure. Theprocedure consists in suspending and tumbling the two layers in currentof air until the wall forming composition surrounds the layers. The airsuspension procedure is described in U.S. Pat. No. 2,799,241; J. Am.Pharm. Assoc., Vol. 48 pp 451-454 (1979); and, ibid, Vol. 49, pp 82-84(1960). Other standard manufacturing procedures are described in ModemPlastics Encyclopedia, Vol 46, pp 62-70 (1969); and in PharmaceuticalScience, by Remington, 14th Ed., pp 1626-1678 (1970), published by MackPublishing Co., Easton, Pa.

Exemplary solvents suitable for manufacturing the wall, the laminatesand laminae include inert inorganic and organic solvents final laminatedwall. The solvents broadly include members selected for the groupconsisting of aqueous solvents, alcohols, ketones, esters, ethers,aliphatic hydrocarbons, halogenated solvents, cycloaliphatics,aromatics, heterocyclic solvents and mixtures thereof. Typical solventsinclude acetone, diacetone, alcohol, methanol, ethanol, isopropylalcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropylacetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone,n-hexane, n-heptaene ethylene glycol monoethyl ether, ethylene glycolmonoethyl acetate, methylene dichloride, ethylene dichloride, propylenedichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane,tetrachoroethan, ethyl ether, isopropyl ether, cyclohexane, cyclooctane,benzene, toluene, naphtha, tetrahydrofuran, diglyme, aqueous andnonaqueous mixtures thereof, such as acetone and water, acetone andmethanol, acetone and ethyl alcohol, methylene dichloride and methanol,and ethylene dichloride and methanol.

The following embodiments are also contemplated by the presentinvention:

(1) A therapeutic composition comprising 0.5 mg to 750 mg of a drug ofthe formula of drug 16, wherein the drug of the formula is blended witha poly(alkylene oxide) polymer.

(2) A therapeutic composition comprising 0.5 mg to 750 mg of a drug ofthe formula of drug 16, wherein the drug of the formula is blended witha cellulose polymer.

(3) A therapeutic composition comprising 0.5 mg to 750 mg of a drug ofthe formula of drug 16, wherein the drug of the formula is blended witha maltodextrin polymer.

(4) A method for administering a drug to the gastrointestinal tract ofan animal, wherein the method comprises: (a) admitting orally into theanimal a dosage form comprising a drug of the formula of1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol which drugpossesses antidepressant therapy and the dosage form comprises a memberselected from the group consisting of a sustained-release dosage formand a controlled-release dosage form; and, (b) administering the drugfrom the dosage form over an extended period of time in atherapeutically responsive dose to produce the antidepressant therapy.

(5) A dosage form for administering a drug to an environment of use,wherein the dosage form comprises a drug of the formula of1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol which dosageform comprises a member selected from the group consisting of asustained-release dosage form and a controlled release dosage form, andwherein said dosage form comprises means for storing the drug and meansfor releasing the drug over an extended period of time.

(6) A dosage form for the oral delivery of a drug to an environment ofuse, wherein the dosage form comprises: (a) a wall comprising at leastin part a composition permeable to the passage of fluid, which wallsurrounds: (b) a compartment; (c) a drug composition in the compartmentcomprising a drug of the formula of drug 16; and (d) a displacement inthe compartment comprising a composition comprising an osmoticallyactive compound; and, (e) an exit passageway in the dosage form fordelivering the drug composition from the dosage form.

(7) A dosage form for the oral delivery of the drug to an environment ofuse according to (6), wherein the drug is1-[2-(dimethylamino)-1(4-me-thoxeyphenyl)ethyl]-cyclohexanol.

DETAILED DISCLOSURE OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and accompanying claims.

Example 1

A dosage form adapted for delivering a drug in a therapeutic range ismanufactured as follows: first a displacement or push layer is preparedby blending and passing through a stainless steel sizing screen having amesh opening of 420 microns 587.5 grams of sodium carboxymethylcellulosehaving a degree of polymerization of approximately 3,200 and a degree ofsubstitution of 0.7 carboxymethyl groups per anhydroglucose unit, 300grams of powdered sodium chloride, 50 grams of hydroxypropylcellulosehaving a molecular weight of approximately 60,000 grams per mole, and 50grams of hydroxypropylmethylcellulose having an average methoxyl contentof 29 weight percent and an average hydroxypropyl content of 10 weightpercent and an average molecular weight of approximately 11,300 gramsper mole. Next 10 grams of red ferric oxide were passed through a sizingscreen having openings of approximately 250 microns. The resultingpowders were mixed in a planetary mixer to a uniform blend. Theresulting blend was wet granulated by adding with stirring anhydrousethyl alcohol until, a cohesive mass was formed. This mass was passedthrough a sizing screen having openings of approximately 840 microns,forming coated displacement particles, which were an dried overnight atambient temperature and humidity. The dried particles were then passedagain through the 840 micron sizing screen. Next 2.5 grams of magnesiumstearate, which had been previously sized through a mesh having 180micron openings, were tumble mixed into the coated particles.

A composition comprising a drug of the structural formula was preparedas follows: first, a drug composition was prepared by passing 840 gramsof venlafaxine hydrochloride, 100 grams of hydroxypropylcellulose havinga molecular weight of approximately 60,000 grams per mole, and 50 gramsof polyvinylpyrrolidone having a molecular weight of approximately40,000 grams per mole, were passed through a sizing having openings ofapproximately 420 microns, and mixed in a planetary mixer to yield auniform blend. Then, anhydrous ethyl alcohol was added to the mixturewith stirring to produce a cohesive damp mass. The resulting damp masswas sized through a sieve having an opening of 840 microns, producingcoated venlafaxine drug, which was air dried overnight. The resultingdried coated venlafaxine drug was passed again through the sizing screenhaving an 840 micron opening. Next, 10 grams of magnesium stearate,sized to 180 microns, was tumble mixed into the blend.

Next, the displacement-push composition and the drug composition wereformed into a bilayer core as follows: first, 87 mg of the drugcomposition was placed in a 9/32 inch round die cavity and lightlytamped with a standard concave round tooling to form a slightly cohesivelayer. Then, 70 mg of push composition was added to the die and theresulting fill was compressed with a final force of 2 tons, therebyforming a two layer cores.

The bilayer cores were placed next in a coating pan having a 12 inchdiameter and they were coated with a wall-forming solution. Thewall-forming solution was prepared by dissolving 380 grams of celluloseacetate having an acetyl content of 39.8 weight percent in 7,220 gramsof acetone. In a separate mixing vessel, 20 grams of polyethylene glycolhaving a molecular weight of approximately 3,350 grams per mole weredissolved in approximately 380 grams of purified water. The twosolutions were mixed to form the wall-coating solution which was spraycoated onto the cores until about 20 mg of wall composition wasdeposited on the surfaces of the bilayer core.

A delivery exit port was formed across the wall by drilling an exitport, centered on the face of the dosage form on the drug compositionside of the dosage form. The resulting dosage form was placed insimulated physiological fluid at 37° C., and the dosage form delivered adose of 73 mg of venlafaxine hydrochloride at a controlled, zero rateover an extended duration of 15 hours.

Example 2

The procedure of Example 1 was followed with the manufacturingprocedures as set forth, except that the drug composition comprises 890grams of venlafaxine hydrochloride, 100 grams of hydroxypropylcellulose,and 10 grams of magnesium stearate. The resulting dosage form releasedin simulated intestinal fluid 77 mg of venlafaxine hydrochloride at azero-order rate over an extended duration of 16 hours.

Example 3

The procedure of Example 1 was followed with all manufacturing steps asdescribed, except that the drug composition consists of 650.0 grams ofvenlafaxine hydrochloride, 240.0 grams of maltodextrin having an averagemolecular weight of approximately 1800 grams per mole and an averagedegree of polymerization of 11.1, 80.0 grams of hydroxypropyl cellulose,20.0 grams of polyvinyl pyrrolidone, and 10.0 grams of magnesiumstearate. The resulting dosage form was tested in artificial intestinalfluid, the dosage form delivered a dose of 57 mg of venlafaxinehydrochloride at zero order rate over a period of 15 hours.

Example 4

The procedure of Example 1 was repeated with the manufacture aspreviously set forth, except that the drug composition consists of 840.0grams of venlafaxine hydrochloride, 150.0 grams of polyethylene oxidehaving an average molecular weight of approximately 100,000 grams permole, and 10.0 grams of magnesium stearate. The wall weight weighedapproximately 25 mg. The resulting dosage forms were tested in simulatedintestinal fluid, and they released a dose of 73 mg of venlafaxinehydrochloride at controlled rate over an extended period of 20 hours.

Example 5

The compositions were manufactured as in Example 1. The process ofmanufacture was the same except that the push layer manufactured wasprepared in a fluid bed aqueous-based granulation process. This wasaccomplished by sizing the sodium carboxymethyl cellulose, the sodiumchloride, the hydroxypropyl cellulose, and red ferric oxide through ascreen having openings of 420 microns. The resulting powders werecharged into a fluid bed granulation column and binder solutionconsisting of the hydroxypropyl methylcellulose at a 5 percent solidsconcentration in water was sprayed on, thereby forming the granules forthe push layer.

Example 6

The compositions and processes followed in this example were the same asin Example 1 except the push consisted of 740.0 grams polyethylene oxidewith an average molecular weight of approximately 5 million grams permole, 200.0 grams of sodium chloride, 50.0 grams of hydroxypropyl methylcellulose having average molecular weight of approximately 11,300 permole, 5.0 grams of red ferric oxide, and 5.0 grams of magnesiumstearate.

DESCRIPTION OF METHOD OF PERFORMING THE INVENTION

Additional embodiments of the invention pertains to a method fordelivering a drug embraced by the structural formula of this inventionfor its intended therapy. One embodiment pertains to a method fordelivering a drug of the formula by administering a dosage formcomprising 0.5 mg to 750 mg of the drug from a dosage form selected fromsustained-release and controlled-release dosage forms in atherapeutically responsive dose over an extended period of time. Anotherembodiment of the invention pertains to a method for delivering a drugof the formula disclosed in this invention, to the gastrointestinaltract of a human in need of this therapy, wherein the method comprisesthe steps of: (A) admitting orally into the gastrointestinal tract ofthe human a dosage form comprising: (1) a non-toxic wall compositioncomprising means for imbibing an external aqueous fluid through the wallinto the dosage form, which wall surrounds and defines; (2) an internalcompartment; (3) a drug composition comprising a drug of the formula inthe compartment comprising a dosage unit amount of said drug; (4) a pushcomposition in the compartment for pushing the drug composition from thecompartment; (5) at least one exit means in the wall for delivering thedrug from the dosage form; (B) imbibing fluid through the wall into thecompartment thereby causing the composition to form a deliverable dosageform and concomitantly causing the push composition to expand and pushthe drug composition through the exit means from the dosage form; and(C) deliver the therapeutic drug in a therapeutically effective amountat a controlled rate over an extended period of time to the patient inneed of said therapy. The method also comprising dispensing a doseamount of said drug from an instant release exterior dosage amount ofdrug to the patient for providing instant anti-depressant therapy.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variations and modifications maybe made herein, in accordance with the inventive principles disclosed,without departing from the scope of the invention.

We claim:
 1. A dosage form having sustained-release orcontrolled-release properties for delivering1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol from thedosage form over an, extended period of time in a therapeuticallyresponsive dose to produce antidepressant therapy, the dosage formcomprising: (a) a wall comprising at least in part a compositionpermeable to the passage of fluid, but not to1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol, which wallsurrounds; (b) a compartment comprising a first layer and a secondlayer; (c) a drug composition in the first layer of the compartmentcomprising 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanoland a hydroxypropylalkylcellulose wherein said alkyl is of 1 to 3carbons or a hydroxyalkylcellulose wherein said alkyl is of 1 to 3carbons; (d) a displacement composition in the second layer of thecompartment comprising an osmotically active compound; and (e) an exitpassageway in the dosage form for delivering the drug composition fromthe dosage form.
 2. A dosage form having controlled-release propertiesfor delivering1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol from thedosage form over an extended period of time in a therapeuticallyresponsive dose to produce antidepressant therapy, the dosage formcomprising: (a) a wall comprising at least in part a compositionpermeable to the passage of fluid, but not to1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol, which wallsurrounds; (b) a compartment comprising a first layer and a secondlayer; (c) a drug composition in the first layer of the compartmentcomprising 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanoland a poly(ethylene oxide) having a molecular weight of 100,000 to600,000; (d) a displacement composition in the second layer of thecompartment comprising an osmotically active compound and apoly(ethylene oxide) comprising the repeating unit (—CH₂—CH₂—O—)_(n),wherein n is a positive whole number of 50,000 to 300,000; and (e) anexit passageway in the dosage form for delivering the drug compositionfrom the dosage form.
 3. A dosage form having sustained-release orcontrolled-release properties for delivering1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol from thedosage form over an extended period of time in a therapeuticallyresponsive dose to produce antidepressant therapy, the dosage formcomprising: (a) a wall comprising at least in part a compositionpermeable to the passage of fluid, but not to1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol, which wallsurrounds; (b) a compartment comprising a first layer and a secondlayer; (c) a drug composition in the first layer of the compartmentcomprising 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanoland a hydroxyalkylcellulose wherein said alkyl is of 1 to 3 carbons; (d)a displacement composition in the second layer of the compartmentcomprising an osmotically active compound; and (e) an exit passageway inthe dosage form for delivering the drug composition from the dosageform.